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Korean J Physiol Pharmacol
Vol 18: 469-474, December, 2014
Alcohol-induced Hyperlipidemia Is Ameliorated by Orally
Administered DWP208, a Sodium Succinate Form of ZYM201
Jae Youl Cho1,*, Jongwon Choi2,*, Jae Gwang Park1, Young-Su Yi1, Muhammad Jahangir Hossen1,3,
Hyeongmin Kim4, Jieun Ro4, Bae Cheon Cha5, Eun Sook Yoo6, Jong-Hoon Kim7, and Jaehwi Lee4
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, 2College of Pharmacy, Kyungsung University, Busan
608-736, Korea, Department of Animal Science, Patuakhali Science and Technology University, Barisal 8602, Bangladesh, College of
Pharmacy, Chung-Ang University, Seoul 156-756, 5College of Health Sciences, Sangji University, Wonju 220-702, 6College of Medicine,
Jeju National University, Jeju 690-756, 7College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Jeonju
561-756, Korea
DW P208 is a sodium succinate form of ZYM-201 which is a triterpenoid glycoside isolated from
Sanguisorba officinalis, a medicinal plant prescribed for various diseases, such as duodenal ulcers and
bleeding in East Asian counties. W e demonstrated that this compound is able to normalize the altered
lipid metabolism induced by hyperglycemia and a high fat diet. In this study, we determined whether
hyperlipidemic conditions induced with chronically treated alcohol can also be restored by DW P208.
Similar to our previous results, orally administered DW P208 (1 to 10 mg/kg) also ameliorated the
hyperlipidemia that was induced by alcohol. This compound reversed the alcohol-induced hyperlipidemia including (i) up-regulated hyperlipidemic parameters such as low-density lipoprotein (LDL),
very low-density lipoprotein (VLDL), atherosclerotic index (AI), triglyceride, and total cholesterol, and
(ii) down-regulated hyperlipidemic parameters such as absolute body weight, superoxide dismutase
(SOD) activity, and high-density lipoprotein (HDL) in serum and liver. According to our data, the
ameliorative activity of DW P208 is due to its indirect anti-oxidative activity as a result of which lipid
peroxide and hydroxyl radical levels were reduced and the activity of SOD was enhanced. Therefore,
our data strongly suggest that DW P208 can be used as a remedy against alcohol-induced hyperlipidemia.
Key W ords: Anti-hyperlipidemic activity, Chronic alcohol treatment, DW P208, Sanguisorba officinalis,
Triterpenoid glycoside
Corresponding to: Jong-Hoon Kim, College of Veterinary Medicine,
Biosafety Research Institute, Chonbuk National University, 567
Baekje-daero, Deokjin-gu, Jeonju 561-756, Korea. (Tel) 82-63-2702563, (Fax) 82-63-270-3780, (E-mail) [email protected], Jaehwi
Lee, College of Pharmacy, Chung- Ang University, 84 Heuksuk-ro,
Dongjak-gu, Seoul 156-756, Korea. (Tel) 82-2-820-5606, (Fax)
82-2-816-7338 (E-mail) [email protected]
*These authors contributed equally to this study.
accumulation in their hepatocytes, a critical process in disease progression leading to late stage hepatitis and cirrhosis [1-3]. Abnormal lipid metabolism includes fat accumulation in the liver caused by an imbalance between the
degradation and synthesis of fatty acids. Development of
hepatic steatosis is therefore initially seen in deleterious
effects of excessive alcohol intake [4-6]. In addition, hypertriglyceridemia (increased blood triglyceride levels) caused
by elevated very low-density lipoprotein and chylomicron
levels in the blood [7], and hypercholesterolemia caused by
enhanced cholesterol biosynthesis and decreased bile acid
excretion [8] were observed in chronic alcohol consumption
DWP208, a sodium succinate form of ZYM-201 (Fig. 1),
is a saponin derivative obtained from a ziyu-glycoside of
Sanguisorba officinalis L. (Rosaceae). This compound has
been reported to be an orally available drug. Orally administered DWP208 dose-dependently inhibited in vivo tissue factor (TF) activity with an ED50 of 1.7 mg/kg [9].
Furthermore, ZYM-201 diminished both in vitro and in vivo
This is an Open Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work
is properly cited.
ABBREVIATIONS: VLDL, very low-density lipoprotein; AI, atherosclerotic index; SOD, superoxide dismutase; TF, tissue factor; TNF,
tumor necrosis factor; TBARS, thiobarbituric acid reactive
substances; HMG, 3-hydroxy-3-methyl-glutaryl.
Chronic ethanol intake is a serious social problem since
it increases social expenses in terms of health and family
problems. Recently, a great increase in the number of Koreans who chronically consume ethanol has been associated
with such problems. One health problem with ethanol intake is dysregulated hepatic lipid metabolism. For example,
patients abusing alcohol are observed to have triglyceride
Received April 25, 2014, Revised September 5, 2014,
Accepted September 5, 2014
JY Cho, et al
DWP208 (0 to 10 mg/kg) or fenofibrate (5 mg/kg) were orally administered once a day for 1 week. According to previous methods [12], animals were anesthetized and blood
was drawn by cardiac puncture 2 h after the final drug
administration. Serum was obtained by centrifugation of
blood at 3,000 rpm for 15 min.
Biochemical analysis of serum
Fig. 1. Chemical structure of DWP208.
tumor necrosis factor (TNF)- production with an IC50 and
ED50 of 69.4 M and 87.4 mg/kg, respectively [9], suggesting
that DWP208 may have therapeutic activity against tissue
TF- and TNF-mediated diseases such as septic shock and
against hyperlipidemic conditions. Indeed, this compound
strongly attenuated the hyperlipidemia induced by diabetic
and high fat diet conditions as did other saponin components from Sapindus rarak DC, floratheasaponins, and
Eugenia jambolana [10]. However, because a major cause
of hyperlipidemia is chronic alcohol intake, we investigated
the curative activity of DWP208 in a rat model of chronic
alcohol consumption.
DWP208, a sodium succinate form of ZYM-201 (ziyuglycoside II methylester) [9], was synthesized by adding succinic
anhydride and sodium-2-ethylhexanoic acid. The yield of
DWP208 was 83% and its chromatographic purity was
greater than 95.3% according to HPLC analysis. Fenofibrate,
cholesterol, (3-4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole (MTT), succinic anhydride, and
sodium-2-ethylhexanoic acid were purchased from SigmaAldrich Chemical Co. (St. Louis, MO, USA). Absolute alcohol was purchased from Fluka (Buchs, Switzerland). All
other chemicals and reagents used were of pharmaceutical
grade. Fetal bovine serum and RPMI1640 were obtained
from GIBCO (Grand Island, NY, USA). RAW264.7 cells
were purchased from ATCC (Rockville, MD, USA).
Male Sprague-Dawley (SD) rats weighing 150-160 g were
purchased from Daehan Biolink (Daejeon, Korea) and were
given ad libitum access to a commercial diet (Samyang,
Korea) and water. They were housed in a temperature-controlled room at 20oC with lighting on for 12 h. Humidity
was maintained between 50 and 70%. Our study was approved by the Animal Ethics Committee of Kangwon
National University (Chuncheon, Korea) and was performed in accordance with the “Guide for the Care and Use
of Laboratory Animals” published by the Korea National
Institute of Health.
Induction of hyperlipidemic conditions
To induce hyperlipidemic conditions, 10% (w/w) aqueous
ethanol was chronically treated for 8 weeks as reported previously [11]. At the end of the treatment, using these rats,
Serum was separated by centrifugation at 1,000 g for 15
min. The levels of total cholesterol, total triglyceride,
high-density lipoprotein (HDL), low-density lipoprotein
(LDL), and very low-density lipoprotein (VLDL) were determined using an automatic analyzer (Hitachi 7020,
Japan) [13]. Determination of hydroxyl radicals was done
by a method previously reported [14]. Lipase activity in serum was also determined by a method previously published
[15]. Lipid peroxidation levels in liver and serum were measured using an assay for thiobarbituric acid reactive substances (TBARS) [16]. SOD activity was assayed in the serum and liver using a technique that involves inhibition
of pyrogallol auto oxidation at pH 8.0 [17].
Biochemical analysis of liver samples
Liver samples for enzymatic analyses were prepared according to the methods of a previous report [18]. Each liver
sample (1 g) was homogenized (10%, w/v) in four volumes
of 0.1 M potassium phosphate buffer (pH 7.5), then centrifuged at 600 g for 10 min, 10,000 g for 20 min, and 105,000
g for 60 min to prepare the microsomal fraction. The microsomal fraction was used for the assay of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase. Total lipids, total cholesterol, and triglyceride in the liver homogenate prepared
with 0.9% NaCl were enzymatically determined using assay
kits (Asan Pharmacy, Seoul, Korea). Protein concentrations
were determined by the Bradford method [19] using BSA
as the standard.
Statistical analysis
Student’s t-test and a one-way ANOVA were used to determine the statistical significance of differences between
values for the various experimental and control groups.
Data are expressed as mean±standard error (SEM) and the
results are taken from at least four independent experiments performed in 10 rats. p<0.05 was considered to be
statistically different unless otherwise indicated.
Since we found that DWP208, a water-soluble salt form
of ZYM-201, is able to normalize the up-regulated levels
of hyperlipidemic parameters in an animal model of streptozotocin-induced diabetes that was simultaneously fed a
high fat diet [20], we examined the effects of DWP208 on
alcohol-induced hyperlipidemia. Chronic alcohol addiction
is more prevalent in the Korean population and causes serious effects such as liver damage, leading to the generation
of fatty liver, cirrhosis, and liver cancer. Although getting
the patient to abstain from alcohol drinking would be ideal,
alcohol-induced liver damage and subsequent malfunction
of liver metabolism, causing the generation of various vascular diseases, such as atherosclerosis and stroke should
Amelioration of Alcohol-induced Hyperlipidemia by DWP208
be restored. To date, no drug has been reported to be a
strong candidate for treating these symptoms of chronic alcohol intake. In the current study, we investigated the possibility that DWP208 can be used as a remedy to ameliorate
alcohol-induced liver dysfunction in an animal model of alcohol-induced hyperlipidemia.
During chronic alcohol (10%) treatment, it has been
shown that liver function and lipid metabolism are altered.
Thus, alcohol treated individuals display striking hyperlipidemic symptoms such as (i) up-regulated levels of LDL,
VLDL, atherosclerosis index (AI), serum triglyceride and
total cholesterol, hepatic total lipid, cholesterol, and triglyceride levels, and serum lipoproteins and HMG-CoA reductase contents (Fig. 2, 3, 4, 5, Table 1), and (ii) down-regulated levels of body weight, HDL, and SOD activity (Table
2, Fig. 2A, and Fig. 5C). The alcohol-induced up-regulation
and down-regulation of these parameters were previously
reported [21,22], indicating that our experimental plan was
Fig. 2. Effect of DWP208 on serum parameters in alcohol-induced
hyperlipidemic rats. (A) Alcohol-treated rats were orally administered with DWP208 or fenofibrate (Feno) for 1 week. After preparing serum from rats, levels of HDL, LDL, and VLDL were
examined. (B) AI values were calculated from an equation [AI=
(total cholesterol-HDL-cholesterol)/HDL-cholesterol]. Data represent mean±SEM of four independent observations performed with
10 rats. #p<0.05 and ##p<0.01 compared to normal group, *p<0.05
and **p<0.01 compared to control group.
Also, DWP208 was able to ameliorate the hyperlipidemia
induced by a high fat diet or streptozotocin [20]. Furthermore, DWP208 protected against the hyperlipidemia induced by chronic alcohol intake. The most striking activity
of DWP208 was its effects on LDL levels. Alcohol-induced
up-regulation of LDL was completely restored by DWP208
treatment at 3 to 10 mg/kg (Fig. 2A). Reduced HDL levels
were also restored and enhanced VLDL level were normalized. Consequently, AI value increased in alcohol treatment was strongly recovered in DWP208 treatment groups
(3 and 10 mg/kg), as standard compound fenofibrate did
(Fig. 2B). DWP208 also attenuated the up-regulated triglyceride and total cholesterol levels in serum (Fig. 3A, Table 1).
To see if the regulation of serum metabolism of lipid molecules by DWP208 was due to modulation of serum lipase
levels, the activity of this enzyme was tested. However,
chronic alcohol treatment failed to significantly increase
the serum activity of lipase (Fig. 3B); indeed, there was
a slight decrease. DWP208 did not alter serum lipase activity, while fenofibrate increased it up to 2 fold, suggesting
that DWP208-mediated regulation of serum parameters is
not serum lipase dependent. In fact, hepatic levels of total
lipid (Fig. 4A), total cholesterol (Fig. 4B), and triglycerides
(Fig. 4C) upregulated by 10% alcohol treatment were apparently restored by DWP208 (Fig. 5), suggesting that altered
hepatic lipid metabolism can be targeted by DWP208. However, HMG-CoA reductase, a critical enzyme for cholesterol
biosynthesis [23], did not appear to be a target enzyme involved in DWP208-mediated amelioration of hyperlipidemic
Fig. 3. Effect of DWP208 on serum parameters in alcohol-induced
hyperlipidemic rats. (A) Alcohol-treated rats were orally administered with DWP208 or fenofibrate (Feno) for 1 week. After preparing serum from rats, levels of triglyceride were examined. (B)
Lipase activity in serum was determined. Data represent
mean±SEM of four independent observations performed with 10
rats. #p<0.05 compared to normal group, *p<0.05 and **p<0.01
compared to control group.
JY Cho, et al
Fig. 4. Effect of DWP208 on hepatic parameters in alcohol-induced
hyperlipidemic rats. (A) Alcohol-treated rats were orally administered with DWP208 or fenofibrate (Feno) for 1 week. After preparing liver homogenates from rats, level of total lipid was examined. (B) Level of total cholesterol in liver was determined. (C)
Level of triglyceride in liver was determined. Data represent the
mean±SEM of four independent observations performed with 10
rats. p<0.01 compared to normal group, **p<0.01 compared to
control group.
conditions. Thus, DWP208 at doses up to 10 mg/kg did not
suppress the activity of this enzyme, although the enhancement of HMG-CoA reductase activity was very marginal
in alcohol treatment group (Table 3), suggesting that other
metabolic enzymes or pathological events could be the target of DWP208.
Since finding a direct target of DWP208 is not easy, we
focused on exploring the effect of this compound on the generation of major pathological molecules. Numerous literature reports have commonly stressed the critical role of
radicals generated during alcohol intake in the malfunction
of hepatic lipid metabolism [5,24]. We found that DWP208
suppresses radical generation under streptozotocin treatment during high fat diet conditions [20]. Indeed, Fig. 5
strongly supported an anti-oxidative role of DWP208 in alcohol-treated conditions. Thus, this compound dose-depend-
Fig. 5. Effect of DWP208 on the contents of lipid peroxide and hydroxyl radicals, and the activity of SOD in serum from alcohol-treated
rats. (A) Alcohol-treated rats were orally treated with DWP208 or
fenofibrate (Feno) for 1 week. After preparing serum, serum lipid
peroxide contents were examined. (B) Hydroxyl radicals were
examined from serum. (C) SOD activity was examined in serum.
Data represent the mean±SEM of four independent observations
performed with 10 rats. #p<0.05 compared to normal group, *p<
0.05 compared to control group.
ently suppressed lipid peroxide (Fig. 5A) content and serum
hydroxyl radical levels (Fig. 5B). Furthermore, the activity
of SOD, an anti-oxidative enzyme against superoxide and
hydroperoxide [25], was restored to normal levels after alcohol treatment had clearly reduced it (Fig. 5C). This suggested that the anti-oxidative property of DWP208 may be
a critical factor in its anti-hyperlipidemic effects.
In general, it has been known that most saponin components are not strong anti-oxidants due to lack of chemical
features [26]. Instead, some saponins such as ginsenoside
Rb1 and gypenosides indirectly protect against cell damage
induced by radicals by suppressing NF- B [27] and increasing glutathione levels [28]. We also failed to find direct neutralizing activity of DWP208 against SNP-induced radical
generation [20]. Therefore, our results and previous reports
suggest that DWP208 is protective by indirectly increasing
Amelioration of Alcohol-induced Hyperlipidemia by DWP208
Table 1. Effect of DWP208 on serum total cholesterol levels in
alcoholic hyperlipidemic rats
Total cholesterol
Rats were orally administered DWP208 (1, 3, or 10 mg/kg) daily
for seven consecutive days after alcohol-induced hyperlipidemia. Rats were sacrificed seven days later. The assay procedure is described in the experimental methods.
Values are expressed mean±SEM (n=4).
Values sharing the same superscript letter are not significantly different from each other (p<0.05) by Duncan's
multiple range test.
Table 2. Effect of DWP208 on body and liver/body weights in
alcoholic hyperlipidemic rats
Absolute body
weight (g)
Table 3. Effect of DWP208 on hepatic HMG-CoA reductase
activity in alcoholic hyperlipidemic rats
Dose (mg/kg)
reductase activity*
The assay procedure is described in the experimental methods.
*HMG-CoA reductase activity: oxidized NADPH pmole/mg protein/min
Values are expressed mean±SEM (n=4).
is increased. Considering that chronic alcohol abuse is a
serious social problem and is increasing particularly fast
in Far East Asian countries, the complications of alcohol
consumption, including hyperlipidemia and atherosclerosis,
will be greatly increased. Our data strongly suggest that
DWP208 can be used as a remedy against alcohol-induced
weight (%)
Rats were orally administered DWP208 (1, 3, or 10 mg/kg) daily
for seven consecutive days after alcohol-induced hyperlipidemia. The assay procedure is described in the experimental
Values expressed are mean±SEM (n=4).
Values sharing the same alphabetical superscript letter were
not significantly different from each other (p<0.05) by Duncan's multiple range test.
cellular anti-oxidant systems. Since various biological activities of saponins - such as acute hepatic failure induced
by lipopolysaccharide and D-galactosamine in mice [29],
gastric ulcer induced by HCl/EtOH [30], and oxidative injury of dopaminergic neurons induced by 1-methyl-4-phenylpyridinium ion (MPP(+) [28] - are derived from their neutralizing activity against oxidative stress, DWP208 seems
to have similar protective activities against these pathological symptoms. Further tests of the pharmacological actions of DWP208 in such models are now warranted.
In summary, we found that orally administered DWP208
can reverse the hyperlipidemia generated by chronic intake
of alcohol. This compound normalized both up-regulated hyperlipidemic parameters such as LDL, VLDL, AI, triglyceride, total cholesterol, and down-regulated hyperlipidemia
parameters such as absolute body weight, SOD activity,
and HDL in serum and liver. According to our data, the
ameliorative activity of DWP208 seems to be due to its indirect anti-oxidative activity by which lipid peroxide and
hydroxyl radical levels are reduced and the activity of SOD
This research was supported by a grant from Sungkyunkwan University (2014).
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